Insulin delivery by implantable micropumps is one approach to the problem of restoration of normoglycemia sufficient to prevent the degenerative sequelae of diabetes. The objective of this proposal is the demonstration that insulin can be delivered by the controlled release micropump (CRM) from an insulin suspension reservoir at both basal and augmented rates in pacreatectomized dogs without refilling the reservoir and thereby restore normoglycemia for longer periods of time than would be possible with a conventional solution reservoir. As proposed, a 2 mL reservoir containing an insulin suspension (insulin crystals suspended in an aqueous buffer) could contain enough insulin for 1-2 years. With the support of NIH and others, 15 animal-months of experience with intrperitoneal insulin delivery (from solutions) have been obtained with implanted CRMs. A delivery program consisting of biphasic augmentation initiated approximately 90 min. after the start of a meal and basal delivery (3 U/day) at other times was found to be sufficient to sustain a reasonable degree of normoglycemia for short periods (1-2 days). No aggregation has been observed in 12 of the animal-months with Hoechst insulin (HOE 21PS) which contains a surfactant to prevent aggregation. We propose to continue to investigate the performace of the CRM in diabetic dogs but now with the reservoir filled with a suspension rather than a solution. Insulin will be delivered intraperitoneally at both basal and augmented rates from the implanted prototype without refilling the reservoir to determine the duration of reliable operation 24 hour glucose and insuling profiles will be used to estimate the in vivo delivery rate. The reservoir fluid will be examined periodically for the presence of aggregates or soluble insulin oligomers, while the tissue after explantation will be examined histologically to determine tissue reaction to the pump outlet. Various insulin formulations and pump outlet designs will be compared in their efficacy to reduce aggregation or control the tissue reaction. With this device, diabetologists and biomedical researchers will be better able to assess the potential benefits to the more than five million diabetics in North America to be derived from open loop insulin delivery systems.